The present invention relates to a series of new derivatives of the known compounds, rhizoxin and its corresponding ring-opened acid. The invention also provides methods and compositions using these compounds as well as processes for their preparation.
Rhizoxin itself is a known compound having the following formula (A): ##STR2## [J. Antibiotics, 37, 354-362 (1984)], and it and its acetate are also known to have an anti-tumor effect [Cancer Res., 46, 381-385 (1986)]. It has also been reported that the mechanism by which it operates is the inhibition of cell division caused by inhibiting the growth of microtubules [J. Antibiotics, 40, 66-73 (1987)]. In accordance with the recommendations of the International Union of Pure and Applied Chemistry, "Nomenclature of Organic Chemistry" Section F, the compounds of the present invention are named as derivatives of rhizoxin and its corresponding ring-opened acid, taking rhizoxin as the base compound and using the numbering system shown on the above formula (A).
Rhizoxin-2-ene was reported on Dec. 18, 1984 to the 1984 International Chemical Congress of the Pacific Basin Society, Honolulu, Hi.
Subsequently, certain specific derivatives of rhizoxin, of rhizoxin-2-ene and of their corresponding ring-opened acids in which the 13-hydroxy group had been acylated by an alkanoyl group having at least 3 carbon atoms were disclosed in U.S. Pat. No. 4,791,128, and were found to have far better anti-tumor activity than rhizoxin and its acetate and a lower toxicity than rhizoxin itself.
We have now discovered an unusual series of rhizoxin derivatives, which, like the compounds of U.S. Pat. No. 4,791,128 are acylated at the 13-position, but which have substantially better activity and lower toxicity.